This invention relates to a method and apparatus for in vivo intradermal incorporation of micro-particles containing encapsulated drugs or a therapeutic agent or cosmetic for topical or subcutaneous application using low frequency ultrasound.
Intradermal delivery of drugs offers several advantages over conventional delivery methods including oral and injection methods. It delivers a predetermined drug dose to a localized area with a controlled steady rate and uniform distribution, is non-invasive, convenient and painless.
U.S. application Ser. No. 09/690,604, commonly assigned and incorporated by reference, describes a method and apparatus for sonoporation of biological barriers such as Stratum Corneum (SC), most commonly referred to as the outermost layer of human skin. Sonoporation is the noninvasive transdermal delivery of pharmaceutical drug molecules through the SC and into the cardiovascular system a human body via ultrasound radiation.
Significant improvement made to existing sonoporation and sonophoresis methods of transdermal drug delivery may be leveraged to increase market share. Drug encapsulation is a known practice in therapeutic application of the potent but very unstable drugs. Using sonoporation and sonophoresis in the area of delivery of encapsulated drugs would provide many additional pharmaceutical benefits compared to the benefits of a present ways of sonoporetic or sonophoresic drug delivery. Some of these benefits would include delivery of peptide-based drugs that range from bed-wetting to gastric bleeding to cancer and immune disorders such as HIV.
In one aspect, the invention provides for an apparatus for sonoporation for intradermal delivery of a microparticles suspension containing microencapsulated drugs including a container having an end covered with a porous membrane and containing the microparticles suspension; an ultrasound horn having a tip submerged in the microparticles suspension containing microencapsulated drugs and applying ultrasound radiation to the microparticles suspension containing microencapsulated drugs wherein the ultrasound radiation is applied at a frequency, an intensity, for a period of time, and at a distance from the skin, effective to generate cavitation bubbles, wherein the cavitation bubbles collapse and transfer their energy into the skin area thus causing the formation of pores in the skin area; and wherein the ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, the ultrasonic jets driving the microparticles suspension containing microencapsulated drugs through a porous membrane and the formed pores into the skin area.
Implementations of the invention may include one or more of the following features. The membranes may have pores with a diameter of 100 micrometers. The ultrasound radiation has a frequency in the range of 1 KHz and 1 MHz. The membrane may be hydrophobic. The tip may be removably connected to the ultrasound horn and it may have a distal end surface, which may be flat or concave. The distal end surface may have a plurality of depressions. The tip may also have a body having markings indicating the amount of microparticles suspension containing microencapsulated drugs contained in the container. A removable protective film may cover the membrane. The container may include an outer wall, an inner wall and an absorbent wick placed between the inner and outer wall. The wick absorbs any excess microparticles suspension containing microencapsulated drugs that is not driven into the skin area through the formed pores and it may be made of highly absorbent and hydrophilic material such as PVA sponge CLINICEL(trademark) from M-Pact Company, HYDROFERA PVA sponge from Hydrofera LLC, Sodium CMC and any other similar spongy material. The container inner wall may have first and second grooves and the tip may have a body having first and second grooves. The tip is inserted into the container and placed so that the first and second grooves of the tip body are opposite the first and second grooves of the container inner wall. This arrangement defines the first and second spaces for accommodating the first and second o-rings, respectively. The container may also have an inlet septum for filling it with the solution. The container may be a cylinder made of a transparent material and/or a plastic material.
The ultrasound frequency may be 20 KHz and the ultrasound intensity may be in the range of 5 W/cm2 and 55 W/cm2. The tip may have a distal end located at a distance from the membrane in the range of 1 millimeter to 10 millimeters. The ultrasound radiation may be continuous or pulsed and it may be applied for a period of time in the range of 30 seconds to 5 minutes, preferably 1 minute for continuous exposure or about 10 to 20 minutes for pulsed exposure with a 5% duty cycle, respectively. The formed pores may have a diameter in the range of 1 micrometer to 100 micrometers.
In another aspect, the invention features a method for sonoporation for intradermal delivery of a microparticles suspension containing microencapsulated drugs. The method includes providing a container containing a predetermined amount of said microparticles suspension containing microencapsulated drugs, or therapeutic agents, or cosmetics and having a first end and a second end, said second end being covered with a porous membrane. Next the tip of an ultrasound horn is submerged in the microparticles suspension containing microencapsulated drugs through the first end of the container and then the porous membrane is placed in contact with said skin area. The ultrasound radiation is applied at a frequency, and intensity, for a period of time, and at a distance from the skin, effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, the ultrasonic jets driving the microparticles suspension containing microencapsulated drugs, therapeutic agents and cosmetics through a porous membrane and the formed pores into the skin area.
In a further aspect, the ultrasound radiation can then applied at a frequency in the range of 1 KHz and 1 MHz.
One advantage of the present invention is to protect against any unknown effects of ultrasound and cavitation on drugs, or therapeutic agents or cosmetics.
A second advantage of the present invention is the controlled release of drugs, or therapeutic agents over time into the stratum corneum and subsequently into the human vascular system. This invention can be used to provide slow and constant intradermal release of drugs, or therapeutic agents or cosmetics.
A third advantage of the present invention is to reduce the need for repeated dosage of drugs, or therapeutic agents since time-released drugs, or therapeutic agents can be administered once and not require repeating for longer periods of time than dosages required using conventional methods.
A fourth advantage of the present invention is the ability to apply sensitive, non-soluble or unstable drugs, or therapeutic agents. Drugs, or therapeutic agents or cosmetics can be specially engineered to retain full potency in a stable environment within the micro-particle until it is delivered using sonoporation. The encapsulation prevents the premature breakdown of drugs or active agents or cosmetic before they can be effectively delivered into or through the skin.
A fifth advantage of the present invention is that the delivery of the drugs and therapeutic agents is painless compared to the side effects or the discomfort and pain associated with injection.